BRONCHOSPASM and INCREASED MORTALITY IN ELDERLY
PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Bronchospasm

ADASUVE can cause bronchospasm that has the potential
to lead to respiratory distress and respiratory arrest. Administer ADASUVE only
in an enrolled healthcare facility that has immediate access on-site to
equipment and personnel trained to manage acute bronchospasm, including
advanced airway management (intubation and mechanical ventilation) [see WARNINGS
AND PRECAUTIONS]. Prior to administering ADASUVE, screen patients regarding a
current diagnosis, history, or symptoms of asthma, COPD and other lung
diseases, and examine (including chest auscultation) patients for respiratory
signs. Monitor for signs and symptoms of bronchospasm following treatment with
ADASUVE [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].

Because of the risk of bronchospasm, ADASUVE is
available only through a restricted program under a Risk Evaluation and
Mitigation Strategy (REMS) called the ADASUVE REMS [see WARNINGS AND PRECAUTIONS].

Elderly patients with dementia-related psychosis
treated with antipsychotic drugs are at an increased risk of death. ADASUVE is
not approved for the treatment of patients with dementia-related psychosis [see
WARNINGS AND PRECAUTIONS].

DESCRIPTION

ADASUVE, a typical antipsychotic, is an inhalation powder
of loxapine supplied in a single-use, disposable inhaler containing 10 mg of
loxapine base. ADASUVE is a drugdevice combination product.

ADASUVE is a single-use, drug-device combination product
that provides rapid systemic delivery by inhalation of a thermally-generated
aerosol of loxapine. Oral inhalation through the product initiates the
controlled rapid heating of a thin film of excipient-free loxapine to form a
thermally-generated drug
vapor. The vapor condenses into aerosol particles that are dispersed into the
airstream created by the patient inhaling through the mouthpiece.

Each product is packaged inside a sealed foil pouch. The
product is a white to off-white plastic unit, with a mouthpiece on one end and
a pull-tab protruding from the other end. Removal of a pull-tab from the
product renders it ready for use, as indicated by illumination of a green
light. After inhalation through the mouthpiece, successful dosing is signaled
by the green light turning off.

Under standardized in vitro test conditions, ADASUVE, 10
mg delivers 9.1 mg of loxapine out of the mouthpiece.

Indications & Dosage

INDICATIONS

ADASUVE is a typical antipsychotic indicated for the
acute treatment of agitation associated with schizophrenia or bipolar I
disorder in adults.

“Psychomotor agitation” is defined in DSM-IV as
“excessive motor activity associated with a feeling of inner tension.” Patients
experiencing agitation often manifest behaviors that interfere with their care
(e.g., threatening behaviors, escalating or urgently distressing behavior,
self-exhausting behavior), leading clinicians to the use of rapidly absorbed antipsychotic
medications to achieve immediate control of the agitation [see Clinical
Studies].

The efficacy of ADASUVE was established in one study of
acute agitation in patients with schizophrenia and one study of acute agitation
in patients with bipolar I disorder [seeClinical Studies].

Limitations Of Use

As part of the ADASUVE REMS Program to mitigate the risk
of bronchospasm, ADASUVE must be administered only in an enrolled healthcare
facility [see WARNINGS AND PRECAUTIONS].

DOSAGE AND ADMINISTRATION

Dosing Information

ADASUVE must be administered only by a healthcare
professional. ADASUVE is administered by oral inhalation only. The
recommended dose for acute agitation is 10 mg administered by oral inhalation,
using a single-use inhaler. Administer only a single dose within a 24-hour
period [see WARNINGS AND PRECAUTIONS].

Required Examination Prior To Dosing

Prior to administering ADASUVE, screen all patients for a
history of asthma, COPD, or other pulmonary disease, and examine patients
(including chest auscultation) for respiratory signs (e.g. wheezing) [see WARNINGS
AND PRECAUTIONS].

Important Administration Instructions

Read all of these instructions prior to administering
ADASUVE.

Step 1. Open the Pouch

When ready to use, tear open the foil pouch and remove
the inhaler from the package (see Figure 1).

Figure 1: Tearing the pouch

When the ADASUVE inhaler is removed from the pouch, the
indicator light is off (see Figure 2).

Figure 2: ADASUVE Inhaler with Indicator Light

Step 2. Pull Tab

Firmly pull the plastic tab from the rear of the inhaler
(see Figure 3). Check that the green light turns on. This indicates that the
inhaler is ready for use. Use the inhaler within 15 minutes after removing the
tab to prevent automatic deactivation of the inhaler. The green light will turn
off, indicating that the inhaler is not usable. Discard the inhaler after one
use.

Figure 3

Step 3. Explain Procedures to the Patient

Explain the administration procedures to the patient
prior to use, and advise the patient that it is important to follow the
instructions. Inform the patient that the inhaler may produce a flash of light
and a clicking sound, and it may become warm during use. These are normal.

Step 4. Instruct the Patient to Exhale

Instruct the patient to hold the inhaler away from the
mouth and breathe out fully to empty the lungs (see Figure 4).

Figure 4: Exhale

Step 5. Instruct the Patient to Inhale

Instruct the patient to put the mouthpiece of the inhaler
between the lips, close the lips, and inhale through the mouthpiece with a
steady deep breath (see Figure 5). Check that the green light turns off
indicating that the dose has been delivered.

Figure 5: Inhale

Step 6. Instruct the Patient to Hold Breath

Instruct the patient to remove the mouthpiece from the
mouth and hold the breath for as long as possible, up to 10 seconds (see Figure
6).

Figure 6: Hold Breath

Important: If the green light remains on after the
patient inhales, the dose of ADASUVE has NOT been delivered. Instruct the
patient to repeat Step 4, Step 5, and Step 6 up to 2 additional times. If the
green light still does not turn off, discard the inhaler and use a new one.

Monitoring To Assess Safety

Monitor the patient for signs and symptoms of
bronchospasm after ADASUVE administration. Perform a physical examination,
including chest auscultation, at least every 15 minutes for at least one hour
after ADASUVE administration [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice. The following
findings are based on pooled data from three short-term (24-hour), randomized,
double-blind, placebo-controlled clinical trials (Studies 1, 2, and 3) of ADASUVE
10 mg in the treatment of patients with acute agitation associated with
schizophrenia or bipolar I disorder. In the 3 trials, 259 patients received
ADASUVE 10 mg, and 263 received placebo [seeClinical Studies].

Commonly Observed Adverse Reactions

In the 3 trials in acute agitation, the most common adverse
reactions were dysgeusia, sedation, and throat irritation. These reactions occurred
at a rate of at least 2% of the ADASUVE group and at a rate greater than in the
placebo group. (Refer to Table 1).

Airway Adverse Reactions In The 3 Trials In Acute
Agitation

Agitated patients with Schizophrenia or Bipolar
Disorder: In the 3 short-term (24-hour), placebo-controlled trials in
patients with agitation associated with schizophrenia or bipolar disorder
(Studies 1, 2, and 3), bronchospasm (which includes reports of wheezing, shortness
of breath and cough) occurred more frequently in the ADASUVE group, compared to
the placebo group: 0% (0/263) in the placebo group and 0.8% (2/259) in the ADASUVE
10 mg group. One patient with schizophrenia, without a history of pulmonary disease,
had significant bronchospasm requiring rescue treatment with a bronchodilator and
oxygen.

Bronchospasm And Airway Adverse Reactions In Pulmonary
Safety Trials

Clinical pulmonary safety trials demonstrated that
ADASUVE can cause bronchospasm as measured by FEV1, and as indicated by
respiratory signs and symptoms in the trials. In addition, the trials
demonstrated that patients with asthma or other pulmonary diseases, such as
COPD are at increased risk of bronchospasm. The effect of ADASUVE on pulmonary
function was evaluated in 3 randomized, double-blind, placebo-controlled clinical
pulmonary safety trials in healthy volunteers, patients with asthma, and
patients with COPD. Pulmonary function was assessed by serial FEV1 tests, and
respiratory signs and symptoms were assessed. In the asthma and COPD trials,
patients with respiratory symptoms or FEV1 decrease of ≥ 20% were
administered rescue treatment with albuterol (metered dose inhaler or
nebulizer) as required. These patients were not eligible for a second dose;
however, they had continued FEV1 monitoring in the trial.

Healthy Volunteers: In the healthy volunteer
crossover trial, 30 subjects received 2 doses of either ADASUVE or placebo 8
hours apart, and 2 doses of the alternate treatment at least 4 days later. The
results for maximum decrease in FEV1 are presented in Table 2. No subjects in
this trial developed airway related adverse reactions (cough, wheezing, chest
tightness, or dyspnea).

Asthma Patients: In the asthma trial, 52 patients
with mild-moderate persistent asthma (with FEV1 ≥ 60% of predicted) were
randomized to treatment with 2 doses of ADASUVE 10 mg or placebo. The second
dose was to be administered 10 hours after the first dose. Approximately 67% of
these patients had a baseline FEV1 ≥ 80% of predicted. The remaining
patients had an FEV1 60-80% of predicted. Nine patients (17%) were former smokers.
As shown in Table 2 and Figure 7, there was a marked decrease in FEV1
immediately following the first dose (maximum mean decreases in FEV1 and %
predicted FEV1 were 303 mL and 9.1%, respectively). Furthermore, the effect on
FEV1 was greater following the second dose (maximum mean decreases in FEV1 and
% predicted FEV1 were 537 mL and 14.7 %, respectively). Respiratory-related
adverse reactions (bronchospasm, chest discomfort, cough, dyspnea, throat
tightness, and wheezing) occurred in 54% of ADASUVE-treated patients and 12% of
placebo-treated patients. There were no serious adverse events. Nine of 26
(35%) patients in the ADASUVE group, compared to one of 26 (4%) in the placebo
group, did not receive a second dose of study medication, because they had a
≥ 20% decrease in FEV1 or they developed respiratory symptoms after the
first dose. Rescue medication (albuterol via metered dose inhaler or nebulizer)
was administered to 54% of patients in the ADASUVE group [7 patients (27%)
after the first dose and 7 of the remaining 17 patients (41%) after the second
dose] and 12% in the placebo group (1 patient after the first dose and 2
patients after the second dose).

COPD Patients: In the COPD trial, 53 patients with
mild to severe COPD (with FEV1 ≥ 40% of predicted) were randomized to
treatment with 2 doses of ADASUVE 10 mg or placebo. The second dose was to be
administered 10 hours after the first dose. Approximately 57% of these patients
had moderate COPD [Global Initiative for Chronic Obstructive Lung Disease
(GOLD) Stage II]; 32% had severe disease (GOLD Stage III); and 11% had mild disease
(GOLD Stage I). As illustrated in Table 2 there was a decrease in FEV1 soon
after the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were
96 mL and 3.5%, respectively), and the effect on FEV1 was greater following the
second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 125 mL
and 4.5%, respectively). Respiratory adverse reactions occurred more frequently
in the ADASUVE group (19%) than in the placebo group (11%). There were no
serious adverse events. Seven of 25 (28%) patients in the ADASUVE group and 1of
27 (4%) in the placebo group did not receive a second dose of study medication
because of a ≥ 20% decrease in FEV1 or the development of respiratory
symptoms after the first dose. Rescue medication (albuterol via MDI or
nebulizer) was administered to 23% of patients in the ADASUVE group: 8% of
patients after the first dose and 21% of patients after the second dose, and to
15% of patients in the placebo group.

Table 2: Maximum Decrease in FEV1 from Baseline in the
Healthy Volunteer, Asthma, and COPD Trials

Maximum % FEV↓

Healthy Volunteer

Asthma

COPD

Placebo
n (%)
N=26

ADASUVE 10 mg
n (%)
N=26

Placebo
n (%)
N=26

ADASUVE 10 mg
n (%)
N=26

Placebo
n (%)
N=27

ADASUVE 10 mg
n (%)
N=25

After any Dose

≥ 10

7 (27)

7 (27)

3 (12)

22 (85)

18 (67)

20 (80)

≥ 15

1 (4)

5 (19)

1 (4)

16 (62)

9 (33)

14 (56)

≥ 20

0

1 (4)

1 (4)

11 (42)

3 (11)

10 (40)

After Dose 1

N=26

N=26

N=26

N=26

N=27

N=25

≥ 10

4 (15)

5 (19)

2 (8)

16 (62)

8 (30)

16 (64)

≥ 15

1 (4)

2 (8)

1 (4)

8 (31)

4 (15)

10 (40)

≥ 20

0

0

1 (4)

6 (23)

2 (7)

9 (36)

After Dose 2

N=26

N=25

N=25

N=17

N=26

N=19

≥ 10

5 (19)

6 (24)

3 (12)

12 (71)

15 (58)

12 (63)

≥ 15

0

5 (20)

1 (4)

9 (53)

6 (23)

10 (53)

≥ 20

0

1 (4)

1 (4)

5 (30)

1 (4)

5 (26)

FEV1 categories are cumulative; i.e. a subject with a
maximum decrease of 21% is included in all 3 categories. Patients with a
≥ 20% decrease in FEV1 did not receive a second dose of study drug.

Figure 7: LS Mean Change from Baseline in FEV1 in
Patients with Asthma

Patients with a ≥ 20% decrease in FEV1 did not
receive a second dose of study drug and are not included in the curves beyond
hour 10.

Extrapyramidal Symptoms (EPS): Extrapyramidal
reactions have occurred during the administration of oral loxapine. In most
patients, these reactions involved parkinsonian symptoms such as tremor,
rigidity, and masked facies. Akathisia (motor restlessness) has also occurred.

In the 3 short-term (24-hour), placebo-controlled trials
of ADASUVE in 259 patients with agitation associated with schizophrenia or
bipolar disorder, extrapyramidal reactions occurred. One patient (0.4%) treated
with ADASUVE developed neck dystonia and oculogyration. The incidence of
akathisia was 0% and 0.4% in the placebo and ADASUVE groups, respectively.

Dystonia (Antipsychotic Class Effect): Symptoms of
dystonia, prolonged abnormal contractions of muscle groups, may occur in
susceptible individuals during treatment with ADASUVE. Dystonic symptoms
include spasm of the neck muscles, sometimes progressing to tightness of the
throat, difficulty swallowing or breathing, and/or protrusion of the tongue.

Acute dystonia tends to be dose-related, but can occur at
low doses, and occurs more frequently with first generation antipsychotic drugs
such as ADASUVE. The risk is greater in males and younger age groups.

DRUG INTERACTIONS

CNS Depressants

ADASUVE is a central nervous system (CNS) depressant. The
concurrent use of ADASUVE with other CNS depressants (e.g., alcohol, opioid
analgesics, benzodiazepines, tricyclic antidepressants, general anesthetics,
phenothiazines, sedative/hypnotics, muscle relaxants, and/or illicit CNS
depressants) can increase the risk of respiratory depression, hypotension, profound
sedation, and syncope. Therefore, consider reducing the dose of CNS depressants
if used concomitantly with ADASUVE.

Anticholinergic Drugs

ADASUVE has anticholinergic activity. The concomitant use
of ADASUVE and other anticholinergic drugs can increase the risk of
anticholinergic adverse reactions including exacerbation of glaucoma and
urinary retention.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Bronchospasm

ADASUVE can cause bronchospasm that has the potential to
lead to respiratory distress and respiratory arrest [see ADVERSE REACTIONS].
Administer ADASUVE only in an enrolled healthcare facility that has immediate
access on-site to equipment and personnel trained to manage acute bronchospasm,
including advanced airway management (intubation and mechanical ventilation) [seeBOXED WARNING and ADASUVE REMS To Mitigate Bronchospasm]. Prior to administering
ADASUVE, screen patients regarding a current diagnosis or history of asthma,
COPD, and other lung disease associated with bronchospasm, acute respiratory symptoms
or signs, current use of medications to treat airways disease, such as asthma or
COPD; and examine patients (including chest auscultation) for respiratory
abnormalities (e.g., wheezing) [SeeDOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].
Monitor patients for symptoms and signs of bronchospasm (i.e., vital signs and
chest auscultation) at least every 15 minutes for a minimum of one hour
following treatment with ADASUVE [seeDOSAGE AND ADMINISTRATION].
ADASUVE can cause sedation, which can mask the symptoms of bronchospasm.

Because clinical trials in patients with asthma or COPD
demonstrated that the degree of bronchospasm, as indicated by changes in forced
expiratory volume in 1 second (FEV1), was greater following a second dose of
ADASUVE, limit ADASUVE use to a single dose within a 24 hour period.

Advise all patients of the risk of bronchospasm. Advise
them to inform the healthcare professional if they develop any breathing
problems such as wheezing, shortness of breath, chest tightness, or cough
following treatment with ADASUVE.

ADASUVE REMS To Mitigate Bronchospasm

Because of the risk of bronchospasm, ADASUVE is available
only through a restricted program under a REMS called the ADASUVE REMS. [seeBOXED WARNING and Bronchospasm] Required components of
the ADASUVE REMS are:

Healthcare facilities that dispense and administer
ADASUVE must be enrolled and comply with the REMS requirements. Certified healthcare
facilities must have on-site access to equipment and personnel trained to
provide advance airway management, including intubation and mechanical
ventilation.

Wholesalers and distributors that distribute ADASUVE must
enroll in the program and distribute only to enrolled healthcare facilities.

Further information is available at www.adasuverems.com
or 1-855-755-0492.

Elderly patients with dementia-related psychosis treated
with antipsychotic drugs are at increased risk of death. Analyses of 17
placebo-controlled trials (modal duration of 10 weeks), largely in patients
taking atypical antipsychotic drugs, revealed a risk of death in drug-treated
patients of 1.6 to 1.7 times the risk of death in placebo-treated patients. Over
the course of a typical 10-week controlled trial, the rate of death in
drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the
placebo group. Although the cases of death were varied, most of the deaths
appeared to be either cardiovascular (e.g., heart failure, sudden death) or
infectious (e.g., pneumonia) in nature. Observational studies suggest that,
similar to atypical antipsychotic drugs, treatment with conventional
antipsychotic drugs may increase mortality. The extent to which the findings of
increased mortality in observational studies can be attributed to the
antipsychotic drug as opposed to some characteristic(s) of the patients is not
clear. ADASUVE is not approved for the treatment of elderly patients with
dementia-related psychosis [see BOXED WARNING].

The diagnostic evaluation of patients with this syndrome
is complicated. It is important to consider the presence of other serious
medical conditions (e.g., pneumonia, systemic infection, heat stroke, primary
CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, or
drug fever).

The management of NMS should include: 1) immediate
discontinuation of antipsychotic drugs and other drugs that may contribute to
the underlying disorder, 2) intensive symptomatic treatment and medical
monitoring, and 3) treatment of any concomitant serious medical problems. There
is no general agreement about specific pharmacological treatment regimens for
NMS.

If a patient requires antipsychotic drug treatment after
recovery from NMS, the potential reintroduction of drug therapy should be
carefully considered. The patient should be carefully monitored, since
recurrences of NMS have been reported.

In the presence of severe hypotension requiring
vasopressor therapy, the preferred drugs may be norepinephrine or
phenylephrine. Epinephrine should not be used, because beta stimulation may
worsen hypotension in the setting of ADASUVE-induced partial alpha blockade.

In short-term (24-hour) placebo-controlled trials of
patients with agitation associated with schizophrenia or bipolar I disorder,
hypotension occurred in 0.4% and 0.8% in the ADASUVE 10 mg and placebo groups,
respectively. There were no cases of orthostatic hypotension, postural
symptoms, presyncope or syncope. A systolic blood pressure ≤ 90 mm Hg
with a decrease of ≥ 20 mm Hg occurred in 1.5% and 0.8% of the ADASUVE 10
mg and placebo groups, respectively. A diastolic blood pressure ≤ 50 mm
Hg with a decrease of ≥ 15 mmHg occurred in 0.8% and 0.4% of the ADASUVE
10 mg and placebo groups, respectively.

In 5 Phase 1 studies in normal volunteers, the incidence
of hypotension was 3% and 0% in ADASUVE 10 mg and the placebo groups,
respectively. The incidence of syncope or presyncope in normal volunteers was
2.3% and 0% in the ADASUVE and placebo groups, respectively. In normal
volunteers, a systolic blood pressure ≤ 90 mm Hg with a decrease of
≥ 20 mm Hg occurred in 5.3% and 1.1% in the ADASUVE and placebo groups,
respectively. A diastolic blood pressure ≤ 50 mm Hg with a decrease of
≥ 15 mm Hg occurred in 7.5% and 3.3% in the ADASUVE and placebo groups,
respectively.

Seizures

ADASUVE lowers the seizure threshold. Seizures have
occurred in patients treated with oral loxapine. Seizures can occur in
epileptic patients even during antiepileptic drug maintenance therapy. In short
term (24 hour), placebo-controlled trials of ADASUVE, there were no reports of
seizures.

Potential For Cognitive And Motor Impairment

ADASUVE can impair judgment, thinking, and motor skills.
In short-term, placebocontrolled trials, sedation and/or somnolence were
reported in 12% and 10% in the ADASUVE and placebo groups, respectively. No
patients discontinued treatment because of sedation or somnolence.

The potential for cognitive and motor impairment is
increased when ADASUVE is administered concurrently with other CNS depressants [see
DRUG INTERACTIONS]. Caution patients about operating hazardous
machinery, including automobiles, until they are reasonably certain that
therapy with ADASUVE does not affect them adversely.

Cerebrovascular Reactions, Including Stroke, In Elderly
Patients With Dementia-Related Psychosis

In placebo-controlled trials with atypical antipsychotics
in elderly patients with dementia- related psychosis, there was a higher
incidence of cerebrovascular adverse reactions (stroke and transient ischemic
attacks), including fatalities, compared to placebo-treated patients. ADASUVE
is not approved for the treatment of patients with dementia-related psychosis [see
BOXED WARNING and Increased Mortality in Elderly Patients with Dementia-Related Psychosis].

Anticholinergic Reactions Including Exacerbation Of Glaucoma
And Urinary Retention

ADASUVE has anticholinergic activity, and it has the
potential to cause anticholinergic adverse reactions including exacerbation of
glaucoma or urinary retention. The concomitant use of other anticholinergic
drugs (e.g., antiparkinson drugs) with ADASUVE could have additive effects.

Patient Counseling Information

Bronchospasm

Advise patients and caregivers that there is a risk of
bronchospasm. Advise patients to inform their healthcare professional if they
develop any breathing problems such as wheezing, shortness of breath, chest
tightness, or cough following treatment with ADASUVE [see BOXED WARNING and
WARNINGS AND PRECAUTIONS]

Interference With Cognitive And Motor Performance

Caution patients and caregivers about performing
activities requiring mental alertness, such as operating hazardous machinery or
operating a motor vehicle, until they are reasonably certain that ADASUVE has
not affected them adversely [see WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a
potentially fatal symptom complex sometimes referred to as NMS has been
reported in association with administration of antipsychotic drugs. Signs and
symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status,
and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND
PRECAUTIONS].

Hypotension And Syncope

Advise patients and caregivers of the risk of hypotension
or orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon
standing) [see WARNINGS AND PRECAUTIONS].

Anticholinergic Reactions

Counsel patients and caregivers about the potential risks
of anticholinergic reactions, such as exacerbation of glaucoma and urinary
retention [see WARNINGS AND PRECAUTIONS].

Pregnancy

Counsel patients and caregivers regarding the potential
risk to the fetus or neonate [see Use In Specific Populations].

Nursing Mothers

Counsel patients and caregivers regarding the potential
risk to the infant [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No adequate studies have been conducted.

Mutagenesis

Loxapine did not cause mutation or chromosomal aberration
when tested in vitro and in vivo. Loxapine was negative in the Ames gene
mutation assay, the human peripheral blood lymphocyte chromosomal aberration
assay, and in the in vivo mouse bone marrow micronucleus assay up to 40 mg/kg
(20-fold the MRHD on mg/m² basis). Loxapine metabolite 8-OH-loxapine was not
mutagenic in the in vitro Ames reverse mutation assay and was not clastogenic
in the in vitro human peripheral blood lymphocyte chromosomal aberration assay.

Impairment Of Fertility

Loxapine had no effects on fertility or early embryonic
development in male rats or in male and female rabbits following oral
administration. Mating was decreased in female rats because these animals were
in persistent diestrus, an expected pharmacologic effect for this class of
compounds. This occurred at doses approximately 0.2- and 1-fold the MRHD of 10
mg/day on a mg/m² basis.

Use In Specific Populations

In general, no dose adjustment for ADASUVE is required on
the basis of a patient's age, gender, race, smoking status, hepatic function,
or renal function.

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies of
ADASUVE use in pregnant women. Neonates exposed to antipsychotic drugs during
the third trimester of pregnancy are at risk for extrapyramidal and/or
withdrawal symptoms following delivery. Loxapine, the active ingredient in
ADASUVE, has demonstrated increased embryofetal toxicity and death in rat
fetuses and offspring exposed to doses approximately 0.5-fold the maximum recommended
human dose (MRHD) on a mg/m² basis. ADASUVE should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.

Human Data

Neonates exposed to antipsychotic drugs during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal
symptoms following delivery. There have been reports of agitation, hypertonia,
hypotonia, tremor, somnolence, respiratory distress, and feeding disorders in
these neonates. These complications have varied in severity; in some cases
symptoms have been self-limited, but in other cases neonates have required intensive
care unit support and prolonged hospitalization.

Animal Data

In rats, embryofetal toxicity (increased fetal
resorptions, reduced weights, and hydronephrosis with hydroureter) was observed
following oral administration of loxapine during the period of organogenesis at
a dose of 1 mg/kg/day. This dose is equivalent to the MRHD of 10 mg/day on a
mg/m² basis. In addition, fetal toxicity (increased prenatal death, decreased
postnatal survival, reduced fetal weights, delayed ossification, and/or
distended renal pelvis with reduced or absent papillae) was observed following
oral administration of loxapine from mid-pregnancy through weaning at doses of
0.6 mg/kg and higher. This dose is approximately half the MRHD of 10 mg/day on
a mg/m² basis.

No teratogenicity was observed following oral
administration of loxapine during the period of organogenesis in the rat,
rabbit, or dog at doses up to 12, 60, and 10 mg/kg, respectively. These doses
are approximately 12-, 120-, and 32-fold the MRHD of 10 mg/day on a mg/m²
basis, respectively.

Nursing Mothers

It is not known whether ADASUVE is present in human milk.
Loxapine and its metabolites are present in the milk of lactating dogs. Because
many drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from ADASUVE, a decision should be made
whether to discontinue nursing or discontinue ADASUVE, taking into account the
importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of ADASUVE in pediatric
patients have not been established.

Geriatric Use

Elderly patients with dementia-related psychosis treated
with antipsychotic drugs are at an increased risk of death [see BOXED
WARNING and WARNINGS AND PRECAUTIONS]. ADASUVE is not approved for
the treatment of dementia-related psychosis. Placebocontrolled studies of
ADASUVE in patients with agitation associated with schizophrenia or bipolar
disorder did not include patients over 65 years of age.

Overdosage & Contraindications

OVERDOSE

Signs And Symptoms Of Overdosage

As would be expected from the pharmacologic actions of
loxapine, the clinical findings may include CNS depression, unconsciousness,
profound hypotension, respiratory depression, extrapyramidal symptoms, and
seizure.

Management Of Overdosage

For the most up to date information on the management of
ADASUVE overdosage, contact a certified poison control center (1-800-222-1222
or www.poison.org). Provide supportive care including close medical supervision
and monitoring. Treatment should consist of general measures employed in the
management of overdosage with any drug. Consider the possibility of multiple
drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor
cardiac rhythm and vital signs. Use supportive and symptomatic measures.

CONTRAINDICATIONS

ADASUVE is contraindicated in patients with the
following:

Current diagnosis or history of asthma, COPD, or other
lung disease associated with bronchospasm [see WARNINGS AND PRECAUTIONS]

Current use of medications to treat airways disease, such
as asthma or COPD [see WARNINGS AND PRECAUTIONS]

History of bronchospasm following ADASUVE treatment [see
WARNINGS AND PRECAUTIONS]

Known hypersensitivity to loxapine or amoxapine. Serious
skin reactions have occurred with oral loxapine and amoxapine.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of loxapine in the treatment of
agitation associated with schizophrenia is unknown. However, its efficacy could
be mediated through a combination of antagonism of central dopamine D2 and
serotonin 5-HT2A receptors. The mechanism of action of loxapine in the
treatment of agitation associated with bipolar I disorder is unknown.

Thorough QTc Study

ADASUVE did not prolong the QTc interval. The effect of
ADASUVE on QTc prolongation was evaluated in a randomized, double-blinded,
positive- (moxifloxacin 400 mg) and placebo-controlled parallel study in
healthy subjects. A total of 48 healthy subjects were administered ADASUVE 10
mg. In this study with a demonstrated ability to detect small effects, the
upper bound of the 90% confidence interval (CI) for the largest
placeboadjusted, baseline-corrected QTc based on individual correction method
was below 10 milliseconds, the threshold for regulatory concern.

Pharmacokinetics

Absorption

The single-dose pharmacokinetic parameters of loxapine
following administration of single doses of ADASUVE 10 mg in healthy adult
subjects are presented in Table 3 and Figure 8.

Administration of ADASUVE resulted in rapid absorption of
loxapine, with a median time of maximum plasma concentration (Tmax) of 2
minutes. Loxapine exposure in the first 2 hours after administration (AUC0-2h)
was 66.7 ng•h/mL for the 10 mg dose. As a consequence of the very rapid
absorption of loxapine after oral inhalation, there is substantial variability
in the early plasma concentrations of loxapine. The mean plasma loxapine concentrations
following administration of ADASUVE were linear over the clinical dose range.
AUC0-2h, AUCinf, and Cmax increased in a dose-dependent manner.

Distribution

Loxapine is removed rapidly from the plasma and
distributed in tissues. Animal studies following oral administration suggest an
initial preferential distribution in the lungs, brain, spleen, heart, and
kidney. Loxapine is 96.6% bound to human plasma proteins.

Metabolism

Loxapine is metabolized extensively in the liver
following oral administration, with multiple metabolites formed. The main
metabolic pathways include: 1) hydroxylation to form 8-OH-loxapine by CYP1A2 and 7-OH-loxapine by CYP3A4
and CYP2D6, 2) N-oxidation
to form loxapine N-oxide by flavanoid monoamine oxidases (FMOs), and 3) de-methylation
to form amoxapine. Because there are multiple metabolic pathways, the risk of
metabolic interactions caused by an effect on an individual isoform is minimal.
For ADASUVE, the order of metabolites observed in humans (based on systemic
exposure) was 8-OH-loxapine > > loxapine N-oxide, 7-OH-loxapine
> amoxapine. Plasma levels of 8-OH-loxapine are similar to those of
the parent compound.

Excretion

Excretion occurs mainly in the first 24 hours.
Metabolites are excreted in the urine in the form of conjugates and in the
feces unconjugated. The terminal elimination half-life (T½) ranged from 6 to 8
hours.

Transporter Interaction

In vitro studies indicated that loxapine was not a
substrate for p-glycoprotein
(P-gp): however, loxapine inhibited P-gp.

Special Populations

Pharmacokinetics in Smokers: Loxapine exposures in
nonsmokers and smokers are similar, with geometric mean ratios of 92%, 85%, and
99% for AUC0-2h, AUCinf, and Cmax respectively. No dosage adjustment is
recommended based on smoking status.

Demographic Effects: There were no clinically
significant differences in loxapine pharmacokinetics following administration
of ADASUVE in subgroups based on age, weight, body mass index, gender, or race.

Animal Toxicology And/Or Pharmacology

In the rat, minimal and reversible squamous metaplasia of
the larynx was observed after daily inhalation exposure of loxapine for 14 days
at 1.7 to 13 mg/kg/day (approximately 2- to 13-fold the MRHD of 10 mg/day on a
mg/m² basis, respectively). This finding was considered a nonspecific particle
impaction effect. Mammary hyperplasia in males and females and ovarian
follicular cysts and mucification of vaginal epithelium in female rats were
observed at all doses, with partial or complete recovery at the end of 14 days
of treatment. In the dog, no effects on the respiratory tract or reproductive
tissues were observed after inhalation exposure to loxapine for 28 days at
doses up to 1.8 mg/kg/day (approximately 6-fold the MRHD of 10 mg/day on a
mg/m² basis).

Clinical Studies

The efficacy of ADASUVE 10 mg in the acute treatment of
agitation associated with schizophrenia or bipolar I disorder was established
in two short-term (24-hour), randomized, double-blind, placebo-controlled,
fixed-dose trials. Study 1 included 344 patients who met DSM-IV criteria for
schizophrenia. Study 2 included 314 patients who met DSM-IV criteria for
bipolar I disorder, manic or mixed episodes with or without psychotic features.

Patients were judged by the clinical investigators to be
clinically agitated, with a level of agitation that met or exceeded a specific
severity threshold as measured by the Positive and Negative Syndrome
Scale-Excited Component (PEC). The PEC is an investigator-rated instrument
consisting of 5 items: poor impulse control, tension, hostility,
uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7
(1 = absent, 4 = moderate, 7 = extreme). Thus, the total PEC score can range
from 5 to 35. For enrollment in the studies, patients had to have a PEC score
of ≥ 14, with at least one individual item score ≥ 4. Patients
whose agitation was related to acute alcohol or drug intoxication were excluded.
Patients with clinically significant acute or chronic pulmonary disease (e.g., asthma,
COPD, chronic bronchitis, and emphysema) were excluded from the trials [See CONTRAINDICATIONS].

The primary efficacy endpoint in both trials was the mean
change from baseline in the PEC score, assessed 2 hours following dosing. The
key secondary endpoint was the mean Clinical Global Impression Improvement
(CGI-I) Scale score at two hours. The CGI-I is an investigator-rated global
assessment of symptom improvement, scored on a scale of 1 to 7: 1 = very much
improved; 4 = no change from baseline; 7 = very much worse. In both studies,
mean baseline PEC scores were similar in all treatment groups, averaging 17.3
to 17.7 (Table 4), with individual patient scores ranging from 14 to 31,
indicating predominantly moderate levels of agitation. The mean baseline
Clinical Global Impression Severity Scale (CGI-S) score in both studies was 4
(moderately ill). In Study 2, 69% of patients had a current manic episode, and
31% had a mixed/manic episode.

In Studies 1 and 2, treatment with ADASUVE was
statistically significantly superior to placebo on the mean change in PEC score
at 2 hours (Table 4). In both studies, the effect of ADASUVE was apparent at 10
minutes following dosing (Figures 9 and 10).

Table 4: Change from Baseline in the PEC Score at 2
Hours Post-Dose in the Schizophrenia (Study 1) and Bipolar I Disorder (Study 2)
Trials

Placebo

ADASUVE

Study 1 (Schizophrenia)

N

115

112

PEC score

Mean baseline

17.4

17.6

Change at 2 hoursa

-5.8

-8.7

Difference from placebo (95% CI)b

--

-2.9 (-4.2, -1.6)

p-value

--

< 0.0001

Study 2 (Bipolar Disorder)

N

105

105

PEC score

Mean baseline

17.7

17.3

Change at 2 hoursa

-4.7

-9.2

Difference from placebo (95% CI)b

--

-4.5 (-5.8, -3.1)

p-value

--

< 0.0001

a Least squares mean for the difference
defined as the change from baselineb Least squares mean for the difference defined as the change from
baseline at hour 2 in the drug group minus that in the placebo group.

Examination of population subsets (age, race, and gender)
on the primary endpoint did not reveal any differential responsiveness on the
basis of these subgroupings.

Figures 9 and 10 show the decreases in PEC score at each
time point assessed in the trials. In both trials, the decrease in agitation
with ADASUVE was apparent at each time point tested (10, 20, 30, 45, 60, 90,
and 120 minutes post-dose).

Figure 9: Mean Change from Baseline in PEC Score
through 2 Hours after a Single Dose in Agitated Patients with Schizophrenia
(Study 1)

Figure 10: Mean Change from Baseline in PEC Score
through 2 Hours after a Single Dose in Agitated Patients with Bipolar Disorder
(Study 2)

The results of the secondary endpoint, CGI-I scores, are
shown in Table 5.

Table 5: CGI-I Score at 2 Hours Post-Dose in the
Schizophrenia and Bipolar I Disorder Trials

Placebo

ADASUVE

Study 1 (Schizophrenia)

N

115

112

CGI-I score at 2 hoursa

2.8

2.1

Difference from placebo (95% CI)

--

-0.8,
(-1.1, -0.4)

p-value

--

< 0.0001

Study 2 (Bipolar Disorder)

N

105

105

CGI-I score at 2 hoursa

3.0

1.9

Difference from placebo (95% CI)a

--

-1.1
(-1.4, -0.8)

p-value

--

< 0.0001

a Least squares mean

Medication Guide

PATIENT INFORMATION

ADASUVE®
(AD-uh-soov)
(loxapine) Inhalation Powder

Read this Medication Guide before you start taking
ADASUVE and each time it is given to you. There may be new information. This
Medication Guide does not take the place of talking to your healthcare provider
about your medical condition or your treatment. You should share this information
with your family members and caregivers.

What is the most important information I should know
about ADASUVE?

ADASUVE is available only through the ADASUVE Risk
Evaluation and Mitigation Strategy (REMS) Program. The healthcare facility must
be enrolled in the ADASUVE REMS Program before you can be given ADASUVE.

ADASUVE may cause serious side effects, including:

Narrowing of the airways (bronchospasm) that can cause
you to have problems breathing or to stop breathing. People who have asthma
or other airway or lung problems, such as chronic obstructive pulmonary disease
(COPD), have a higher risk of bronchospasm when taking ADASUVE. Symptoms of
bronchospasm may include:

shortness of breath
Tell your healthcare provider right away if you have any of these symptoms of
bronchospasm after taking ADASUVE.
Your healthcare provider should check you for breathing problems before and
after you take ADASUVE.

Increased risk of death in elderly patients with
dementia-related psychosis. Medicines like ADASUVE can raise the risk of
death in elderly people who have lost touch with reality (psychosis) due to
confusion and memory loss (dementia). ADASUVE is not approved for the treatment
of patients with dementia-related psychosis.

Tell your healthcare provider if you have any side effect
that bothers you or that does not go away.

These are not all the possible side effects of ADASUVE.
For more information ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use
of ADASUVE.

Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide.

This Medication Guide summarizes the most important
information about ADASUVE. If you would like more information, talk to your
healthcare provider. You can ask your pharmacist or healthcare provider for
information about ADASUVE that is written for health professionals.

For more information, go to www.ADASUVE.com or call
1-888-483-8279.

What are the ingredients in ADASUVE?

Active Ingredient: loxapine

Inactive Ingredients: none

This Medication Guide has been approved by the U.S. Food
and Drug Administration.

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.